Development of a vaccine to prevent, or reduce the rate of, HIV infections remains a high priority despite recent setbacks in the field. The lessons from failed and successful experimental programs indicate the need to apply new approaches to HIV vaccine design with the goal of inducing immune responses that are the appropriate type, quality, magnitude and active in the appropriate sites in the body. A promising approach is the use of the Adenovirus (serotype 4) as a vaccine delivery vehicle. The Ad4 virus was a component in the US Military adenovirus vaccine which was formulated for administration in an oral dosage form. Oral delivery should be advantageous for HIV vaccines because this route of administration is more likely to induce mucosal immune responses than parenteral injection and would target the gut mucosal tissues in particular. The Ad4 vaccine vector is replication competent which should drive the induction and expansion of responses that are different, in terms of magnitude and effector functions, than those induced by non-replicating vectors. In this proposal we outline a one year plan to construct and test experimental live Ad4 vectored vaccines. Up to six Ad4 vectored vaccines will be engineered to encode HIV env proteins for the purpose of inducing antibody responses broadly effective against a variety of HIV strains. The vectored vaccines will then be tested in rabbits to assess neutralizing antibody responses that are effective against a range of HIV isolates, and antibody-dependent cell-mediated virus inhibition of HIV. Mucosal vaccine delivery will also be assessed using oral administration. As designed the initial phase of this SBIR program will provide sufficient data to determine the utility of this Ad4 vector system for inducing effective antibody responses and potentially could yield an experimental vaccine suitable for further testing in nonhuman primates and potentially clinical development. PUBLIC HEALTH RELEVANCE: The development of a safe and protective vaccine against the Human Immunodeficiency Virus (HIV) that causes AIDS has been very difficult. The proposed research will modify an existing adenovirus vaccine, which was used safely in more than 10 million people, so that it expresses HIV proteins and induces an immunological response in animals. This vaccine will have advantages of being live virus vaccine, such as the polio or measles vaccines, which can be taken by mouth without risk of causing HIV infection.